Our long term objective is to gain a better understanding of the etiology of diabetes. Specifically, by investigating the role of glutathione-insulin transhydrogenase (GIT) in the process of insulin degradation we are examining the possibility that some forms of diabetes may be caused by a relative deficiency of insulin caused by increased insulin destruction. The enzyme GIT promotes the degradation of insulin by cleaving the hormone at disulfide bonds. Six GITs from four different organs of three different species have been purified; from four, highly purified preparations have been obtained. All the 6 GITs appear to have remarkably similar physical, enzymatic, kinetic and immunological properties. The enzyme's properties, substrate specificity, kinetics, mechanism of action, and structure are being studied. Its physiological role and how its activity and biosynthesis are controlled in normal, diabetic as well as in prediabetic subjects will be studed. In another phase of the work the chemical properties and possible physiological role(s) of pure A and B chains of insulin will be studied.